CRF neurons of the extended amygdala and alcohol drinking

扩展杏仁核的 CRF 神经元和饮酒

基本信息

批准号：
10189451
负责人：
ROBERT O. MESSING
金额：
$ 34.65万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189451
关键词：
Address Affinity Alcohol consumption Amino Acids Amygdaloid structure Animals Automobile Driving Bacterial Artificial Chromosomes Behavior Behavioral Biology Brain region CRH gene Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Dorsal Enterobacteria phage P1 Cre recombinase Ethanol Ethanol dependence FDA approved Gene Expression Profiling Genetic Goals Growth Associated Protein 43 Heavy Drinking Human Hypothalamic structure Immunoprecipitation Intervention Knowledge Laboratories Lateral Limbic System Literature Maintenance Messenger RNA Modeling Molecular Naltrexone Negative Reinforcements Neurons Neuropeptides Neurotensin Neurotransmitters Peptides Pharmaceutical Preparations Pharmacology Phase Phenotype Physiological Play Population Procedures Property Public Health RNA Interference Rattus Relapse Ribosomes Rodent Role Somatostatin Source Stress Structure of terminal stria nuclei of preoptic region Testing Therapeutic Transgenic Organisms Translating Viral Vector Wistar Rats Withdrawal acamprosate alcohol abuse therapy alcohol craving alcohol measurement alcohol use disorder base designer receptors exclusively activated by designer drugs drinking drug testing experimental study gamma-Aminobutyric Acid knock-down neurobiological mechanism next generation pro-corticotropin releasing hormone prodynorphin promoter psychosocial release factor response sex sexual dimorphism small hairpin RNA success synergism tool transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY Alcohol use disorder is a major public health problem. To date, available treatment options are limited to psychosocial intervention, three FDA approved medications (disulfuram, acamprosate, and naltrexone) and a few drugs approved for other indications, all with relatively small effect sizes. There is a clear need for additional treatments based on a deeper understanding of neurobiological mechanisms. Corticotrophin releasing factor (CRF) is a 41-amino acid neuropeptide produced mainly by neurons of the paraventricular hypothalamus, central amygdala (CeA), and bed nucleus of the stria terminalis (BNST) where it plays an important role in behavioral and physiological responses to stress. CRF has been long implicated in driving excessive ethanol consumption through prior studies that used CRF receptor antagonists in rodents. However, recent attempts to test CRF receptor antagonists as treatments for alcohol craving in humans have been disappointing. Part of this lack of success may be due to inadequate drug-like properties of some compounds and by a need for different human laboratory models that test drug effects on withdrawal and negative reinforcement in dependent subjects. Another reason may be due to the fact that CRF is released from neurons with other peptides and neurotransmitters that may act in synergy to drive excessive drinking. Understanding which of these co-released factors is important necessitates a different strategy that focuses on the CRF neurons themselves rather than on CRF receptors. The lack of genetic access to subpopulations of CRF neurons has made it difficult to study the biology of CRF neurons, the sources of CRF in different brain regions, and the circuitry underlying CRF-regulated behaviors. To fill this gap, we generated a BAC transgenic Wistar rat line in which Cre recombinase is expressed from the Crh gene promoter to enable genetic access to CRF neurons. In this project, we will use these rats to pursue the hypothesis that as animals develop ethanol dependence, CRF neurons in the CeA and BNST promote ethanol consumption through the coordinated release of GABA, CRF, and other neuropeptides. We will examine this hypothesis by selectively activating or inhibiting these neuronal populations and their projections using chemogenetic tools, and we will address the relative importance of the different transmitters and modulators released from these neurons using Cre-dependent RNA interference. Finally, we will investigate the role of repeated ethanol consumption on the transcriptome of these CRF neuronal populations to understand how ethanol changes their phenotype, which should provide us with important new clues as to how they drive excessive drinking. !

项目摘要饮酒障碍是一个主要的公共卫生问题。迄今为止，可用的治疗选项仅限于社会心理干预，三种FDA批准的药物（二硫代，丙霉菌和纳曲酮）和A 很少有批准其他适应症的药物，所有药物的作用大小相对较小。显然需要基于对神经生物学机制的更深入了解的其他治疗方法。皮质营养素释放因子（CRF）是一种41-氨基酸神经肽，主要由脊髓环状神经元产生下丘脑，中央杏仁核（CEA）和质子末端的床核（BNST）在对压力的行为和生理反应中的重要作用。 CRF长期以来一直涉及驾驶通过在啮齿动物中使用CRF受体拮抗剂的先前研究，过度消耗乙醇。然而，最近试图测试CRF受体拮抗剂作为人类饮酒的治疗方法令人失望。缺乏成功的一部分可能是由于某些化合物的毒品样性能不足并且需要测试药物对戒断和阴性影响的不同人类实验室模型依赖主题的加强。另一个原因可能是由于CRF从具有其他肽和神经递质的神经元可能会以协同作用来驱动过量饮酒。了解这些共同发行的因素中的哪些是重要的，需要采取不同的策略，重点是 CRF神经元本身而不是CRF受体。缺乏CRF神经元亚群的遗传获取使得很难研究CRF的生物学神经元，不同大脑区域中CRF的来源以及CRF调节行为的基础电路。为了填补这一空白，我们产生了一个BAC转基因Wistar大鼠系，其中Cre Rebombinase从 CRH基因启动子使遗传获得CRF神经元。在这个项目中，我们将使用这些老鼠追求当动物发展乙醇依赖性时，CEA中的CRF神经元和BNST促进了这一假设通过GABA，CRF和其他神经肽的协调释放，乙醇消耗。我们将通过选择性激活或抑制这些神经元种群及其预测来检查这一假设使用化学发生工具，我们将解决不同发射器和使用CRE依赖性RNA干扰从这些神经元释放的调节剂。最后，我们将调查反复消耗乙醇对这些CRF神经元种群转录组的作用了解乙醇如何改变其表型，这应该为我们提供有关如何的重要新线索他们驾驶过多的饮酒。呢

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Corticosteroid sensitization drives opioid addiction.

DOI：
10.1038/s41380-022-01501-1
发表时间：
2022-05
期刊：
MOLECULAR PSYCHIATRY
影响因子：
11
作者：
Carmack, Stephanie A.;Vendruscolo, Janaina C. M.;McGinn, M. Adrienne;Miranda-Barrientos, Jorge;Repunte-Canonigo, Vez;Bosse, Gabriel D.;Mercatelli, Daniele;Giorgi, Federico M.;Fu, Yu;Hinrich, Anthony J.;Jodelka, Francine M.;Ling, Karen;Messing, Robert O.;Peterson, Randall T.;Rigo, Frank;Edwards, Scott;Sanna, Pietro P.;Morales, Marisela;Hastings, Michelle L.;Koob, George F.;Vendruscolo, Leandro F.
通讯作者：
Vendruscolo, Leandro F.

The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target?